Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply

Houyi Sun,Weicheng Zhang,Hongzhi Wang,Feng Zhu,Ning Yang,Yaozeng Xu,Kai Zheng,Tianhao Wang,Yi Xue,Wei Xu,Dechun Geng,Huilin Yang,Yijun Wang

doi:10.1038/s41419-021-04313-3

Abstract

In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

Highlights

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) is a disabling joint disease that could affect patients of all ages, and typically requires total hip arthroplasty as the end-stage treatment [1, 2]
By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of cannabinoid receptor 2 (CB2) in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms
Given that the Wnt/β-catenin pathway plays a vital role in the regulation of osteogenesis [32], interest (ROI) in the weight-bearing area, we found that the mean bone mineral density (BMD) of MP group (0.238 ± 0.021 g/cm3) was significantly lower than normal group (0.471 ± 0.019 g/cm3)

Summary

Introduction

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) is a disabling joint disease that could affect patients of all ages, and typically requires total hip arthroplasty as the end-stage treatment [1, 2]. From the perspective of bone metabolism, GC-induced ONFH is a disease of focal bone loss, in which osteogenic activity of osteoblasts play an important role. There were findings providing evidence that GC-induced bone disease arises from changes in the numbers of bone cells [17]. Teriparatide as osteogenesis booster has been proved to be superior on bone mineral density (BMD) and osteoporotic fracture risk in GC-treated patients [18]. GCs are reported to directly damage endothelial cells and impair blood supply to bone tissue [4]. All these factors may lead to weaken the osteogenesis in GC-induced ONFH

Methods

Results

Conclusion